RESUMEN
Three-dimensional structure models of the ligand-binding domain of the ecdysone receptor of Heliothis virescens were built by the homology modeling technique from the crystal structures of nuclear receptors. Two models were created based both on known ligand-binding domain structures of the receptors with the highest sequence identity to the ecdysone receptor, and on those of steroid hormone receptors. The latter model, which was found to have better stereochemical quality and be in good agreement with the binding of the steroidal framework of the endogenous agonist 20-hydroxyecdysone, was used for docking studies. The docking of 20-hydroxyecdysone to the receptor model revealed that the ligand molecule can interact with the receptor in a similar manner to other steroid hormone-receptor complexes. The docking of a dibenzoylhydrazine agonist, chromafenozide, was performed based on the correspondences between the molecule and 20-dydroxyecdysone expected by molecular comparison. The interactions of the ligands with the receptor in the complexes modeled were investigated and found to be consistent with known structure-activity relationships.
Asunto(s)
Proteínas de Insectos/química , Modelos Moleculares , Receptores de Esteroides/química , Secuencia de Aminoácidos , Animales , Benzopiranos/química , Benzopiranos/farmacología , Sitios de Unión , Unión Competitiva , Ecdisterona/química , Ecdisterona/farmacología , Hidrazinas/química , Hidrazinas/farmacología , Proteínas de Insectos/agonistas , Proteínas de Insectos/genética , Datos de Secuencia Molecular , Estructura Molecular , Mariposas Nocturnas/química , Mariposas Nocturnas/genética , Conformación Proteica , Receptores de Esteroides/agonistas , Receptores de Esteroides/genética , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
The N'-benzoyl group of N-tert-butyl-N'-benzoyl-3,5-dimethylbenzohydrazide (1) was converted to a series of benzoheterocyclecarbonyl groups in order to investigate the potential usefulness of superimposing a hydrazine insecticide on 20-hydroxyecdysone. A series of analogues with benzodioxole, benzodioxane, benzodioxapine, indole, benzoxazole, benzoxazine or benzothiazole instead of the phenyl group of (1) were synthesized and tested for their insecticidal activity against the common cutworm (Spodoptera litura F). N-tert-Butyl-N'-(3,5-dimethylbenzoyl)-1,3-benzodioxole-5-carbohydrazide and N-tert-butyl-N'-(3,5-dimethylbenzoyl)-2,3-dihydro-1,4-benzodioxine-6-carbohydrazide showed high insecticidal activities, superior to that of (1) and equal to that of the commercial insecticide tebufenozide (RH-5992).
Asunto(s)
Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Hidrazinas/química , Insecticidas/síntesis química , Insecticidas/farmacología , Animales , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/toxicidad , Hidrazinas/farmacología , Hidrazinas/toxicidad , Insecticidas/química , Insecticidas/toxicidad , Larva/efectos de los fármacos , Estructura Molecular , Spodoptera/efectos de los fármacosRESUMEN
A series of N'-benzoheterocyclecarbonyl-N-tert-butyl-3,5-dimethylbenzohydrazide analogues possessing a variety of substituents on the benzene rings of the benzoheterocyle moieties were synthesized and tested for their insecticidal activity. The introduction of a methyl group at the R1 position of the benzoheterocycle moiety strongly increased the insecticidal activity. Among the analogues synthesized, N'-tert-butyl-N'-(3,5-dimethylbenzoyl)-5-methyl-6-chromanecarbohydrazide showed the highest insecticidal activity (LC50 = 0.89 mg litre(-1)).
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/toxicidad , Hidrazinas/química , Insecticidas/síntesis química , Insecticidas/toxicidad , Animales , Compuestos Heterocíclicos/química , Insecticidas/química , Larva/efectos de los fármacos , Dosificación Letal Mediana , Estructura Molecular , Spodoptera/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Nineteen analogues were synthesized by modifying the tert-butylhydrazine moieties of N'-tert-butyl-N'-(3,5-dimethylbenzoyl)-5-methyl-2,3-dihydro-1,4-benzodioxine-6-carbohydrazide and N'-tert-butyl-N'-(3,5-dimethylbenzoyl)-5-methylchromane-6-carbohydrazide (chromafenozide), and the synthesized analogues were evaluated for their insecticidal activity against Spodoptera litura F. While all of the synthesized analogues had insecticidal activity inferior to those of the lead compounds, several of the analogues nonetheless showed high insecticidal activity. Chromafenozide has shown very high selectivity toward lepidopteran species.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/toxicidad , Hidrazinas/química , Insecticidas/síntesis química , Insecticidas/toxicidad , Animales , Benzopiranos/química , Benzopiranos/farmacología , Compuestos Heterocíclicos/química , Hidrazinas/farmacología , Insecticidas/química , Larva/efectos de los fármacos , Dosificación Letal Mediana , Estructura Molecular , Spodoptera/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Chromafenozide (ANS-118) is a non-steroidal ecdysone mimic and its insecticidal effect is highly specific to lepidoptera. In order to evaluate the transcription-inducing activity via nuclear ecdysone receptor (EcR) and the mode of action of chromafenozide, ecdysone-responsive reporter gene assay systems were developed in Sf9 and Kc cells. Ponasterone A, a full EcR agonist, induced reporter transcription in a dose-dependent manner in both Sf9 and Kc cells. In contrast, chromafenozide activated reporter transcription with comparable potency to ponasterone A only in Sf9 cells, although its maximum activity was 4-fold lower than that of ponasterone A. When chromafenozide was applied together with ponasterone A to Sf9 cells, it antagonized ponasterone A at nanomolar concentrations. These results suggest that chromafenozide is a potent partial EcR agonist specific to lepidoptera; it appears to bind lepidopteran EcR with comparable affinity to ponasterone A, but may activate the EcR in a different manner.
Asunto(s)
Benzopiranos/farmacología , Ecdisona/agonistas , Ecdisterona/análogos & derivados , Hidrazinas/farmacología , Spodoptera/efectos de los fármacos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Drosophila melanogaster/citología , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/metabolismo , Ecdisterona/antagonistas & inhibidores , Ecdisterona/farmacología , Inducción Enzimática/efectos de los fármacos , Genes Reporteros/efectos de los fármacos , Genes Reporteros/fisiología , Insecticidas , Lepidópteros , Luciferasas/genética , Luciferasas/metabolismo , Receptores de Esteroides/agonistas , Especificidad de la Especie , Spodoptera/citología , Spodoptera/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
We have investigated the biologically active conformation of the non-steroidal ecdysone agonist, 1-tert-butyl-1,2-dibenzoylhydrazine (RH-5849) by means of design, synthesis and conformational analysis of cyclic derivatives of RH-5849. Among the synthesized compounds, a 6-membered cyclic hydrazine bearing two benzoyl groups (5) exists in three conformational states in solution, and the major unsymmetrical conformer of 5 is similar to that of RH-5849 on the basis of 1H NMR and X-ray analyses. The 3,3-dimethyl derivative of 5 (10) exists as a single unsymmetrical conformer. Although there is conformational similarity of the cyclic derivatives with RH-5849, these compounds did not show any hormonal or insecticidal activity. The hydrogen bonding character of the amide N-H group of the dibenzoylhydrazine seems to play a critical role in the appearance of the biological activity.